The invention concerns a new chemical compound which can be used as a marker substance in kidney diagnostics, its production and use as well as a renal diagnostic agent containing this compound.
Fructans are used among others as marker substances in renal diagnostics and in particular to determine the glomerular filtration rate (GFR) as a test for kidney function. Fructans, which are also known as polyfructosans, are oligosaccharides and polysaccharides which are composed of straight-chained or branched fructose chains which are grafted onto a sucrose base molecule. Depending on the degree of branching of the fructose chains and on the degree of polymerization, the various fructans can have different physical properties such as different water solubilities. Many fructans occur in plants as carbohydrate reserves for example in the subterranean parts of composites, Campanulacaea, grasses and Liliacaea.
The fructans inulin and sinistrin are used in particular as marker substances in the kidney function test. Inulin and sinistrin are each composed of ca. 10 to 40 fructose units and have corresponding molecular weights of ca. 1600 to ca. 6500. After parenteral administration, inulin and sinistrin are neither changed by metabolism nor are they stored in the organism but are filtered out by the kidney glomeruli and are not reabsorbed again in the tubuli.
In order to assess renal function it is usual to determine the time course of the concentration of the marker substance in the blood after parenteral administration of a certain dose of the marker substance. The concentration of the marker substance in the blood can for example be determined by enzymatic methods (cf. e.g. H. F. Kuehnle et al., Fully enzymatic inulin determination in small volume samples without deproteinization, Nephron 62 (1992) 104–107). In the case of inulin as a marker substance, the possibility of using inulin provided with a fluorescent label such as fluroescein isothiocyanate-labelled inulin (FITC-inulin) and determining the concentration of the marker substance by measuring the fluorescence has also been described among others (cf. e.g. M. Sohtell et al., FITC-inulin as a kidney tubule marker in the rat, Acta Physiol. Scand. 119 (1983) 313–316; J. N. Lorenz & E. Gruenstein, A simple, nonradioactive method for evaluating single-nephron filtration rate using FITC-inulin, Am. J. Physiol. 276 (Renal Physiol. 45) (1999) F172–F177).
A disadvantage of inulin and FITC-inulin for the daily clinical routine is that they are only very slightly soluble in water and crystallize in aqueous preparations during storage. Hence the preparations containing inulin usually have to be heated before administration in order to redissolve the inulin or FITC-inulin. However, this procedure hydrolytically attacks the inulin depending on the duration of the heating and the inulin is partially degraded to fructose. Furthermore residues of undissolved inulin particles remain in the preparation when it is incompletely dissolved and these are difficult to detect and can result in severe circulatory complications after an injection. The low solubility of inulin and FITC-inulin make it difficult to achieve a defined concentration of the marker substance in an injection solution. Moreover the administration of inulin and FITC-inulin result in a transient reduction in blood pressure after injection into an experimental animal. In the best case this circulatory reaction lasts five minutes. The circulatory collapse impairs especially the renal function which is to be determined.
Sinistrin is a fructan like inulin and can be obtained by extraction from parts of plants containing fructan (cf. e.g. EP-B 0 568 574). However, the use of sinistrin as a marker substance requires relatively high concentrations of sinistrin in the corresponding preparations which are in a range of 100 mg per kg body weight of the individual to be examined since sinistrin itself can only be determined in blood samples and the analytical methods that are available for this are relatively insensitive. Furthermore sinistrin can only be detected by a multistep enzymatic reaction in which, after removing endogenous glucose, sinistrin is firstly converted into glucose and the glucose obtained in this manner is determined as a measure for sinistrin. Experience has shown that such multistep reactions are complicated and are often very inaccurate.
Hence the object of the present invention is to eliminate the disadvantages of the prior art. In particular an object of the present invention is to provide a substance which can be used as a marker substance in a renal function test and which has advantages over the marker substances known in the prior art and in particular inulin, FITC-inulin and sinistrin.
The object is achieved by the subject matter of the invention as stated in the patent claims.